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Exploring Bell nonlocality with extremal non-signaling boxes
No full textExtremal non-signaling (ENS) boxes are correlations that correspond to vertices of the non-signaling polytope of a Bell scenario. Neither quantum theory nor any theory for ideal measurements allows for ENS boxes. That is, according to quantum theory, ENS boxes are nonphysical. Still, ENS boxes are crucial for addressing a number of problems in Bell nonlocality. Here, we obtain ENS boxes in arbitrary bipartite Bell scenarios and present the complete list of ENS boxes for several unexplored scenarios. Equipped with the boxes, we revisit several foundational questions. We find that already two copies of any ENS box violate the exclusivity (or local orthogonality) and Specker's principles. We provide the minimal decomposition of the magic square correlation-the simplest known perfect correlation in nature-in terms of ENS boxes. We identify the minimal scenario in which a dit of communication (with d ⩽ 5) is insufficient to simulate ENS boxes. Our results show that the ENS boxes approach leads to new results and opens new avenues for research
Cholesterol Remodeling by CH25h Rewires IFITM3 Trafficking and Secretion Without Enhancing Antiviral Restriction
No full textInternational audienceType I interferon induces multiple protein effectors to inhibit viral replication. Among these, the interferon-induced transmembrane protein (IFITM3) and the cholesterol-25-hydroxylase (CH25h) converge on the inhibition of viral entry by altering the behavior of membranes. Here, we dissect the functional and mechanistic relationship between these two membrane-acting effectors using HIV-1 and vesicular stomatitis virus (VSV) as models. We show that IFITM3 and CH25h restrict viral entry with similar efficiency, but act in a largely redundant manner during infection. Their redundancy is consistent across infection systems, cell types, and entry assays, indicating that both factors converge on a shared biophysical block to membrane fusion. Unexpectedly, we uncover a second layer of interplay in which the CH25h-25HC axis remodels IFITM3 trafficking. Exposure to 25-hydroxycholesterol drives IFITM3 from endolysosomal compartments to the plasma membrane, impairs its internalization into early endosomes, and increases its secretion in exosomal vesicles. These effects occur independently of direct antiviral activity and reveal that CH25h regulates IFITM3 cellular dynamics. Together, our study identifies a previously unrecognized cross-regulatory circuit between two IFN-induced antiviral pathways, highlighting how lipid remodeling by CH25h, and potentially by other cellular factors, can contribute to control the behavior of IFITM3. Importance Type I interferons induce numerous antiviral factors that frequently target the same vulnerable steps of viral infection, but how these factors influence one another is not well understood. IFITM3 and the CH25h are two potent, broad-acting inhibitors of viral membrane fusion. Here, we show that although their antiviral activities are largely redundant against HIV-1 and VSV, CH25h profoundly alters the biology of IFITM3. The product of the enzymatic activity of CH25h, the oxysterol 25HC, redistributes IFITM3 from endosomal compartments to the plasma membrane and enhances its release in exosomal vesicles— effects independent of direct antiviral activity. These findings reveal an unexpected layer of cross-regulation between lipid-modifying enzymes and membrane-embedded restriction factors. More broadly, they highlight how interferon-driven lipid remodeling can reshape the trafficking and secretion of antiviral proteins, expanding the functional landscape of innate immunity beyond viral entry inhibition
Phase I(b) study evaluating the safety and efficacy of intratumoral agonistic anti-CD40 (selicrelumab) in combination with anti-PD-L1 (atezolizumab) in patients with refractory or relapsed B-cell lymphoma (ITSELF trial)
No full textInternational audienceBACKGROUND: The efficacy of immune checkpoint blockade therapy requires pre-existing antitumor immunity. Defective antigen presentation during the priming phase can reduce the generation of tumor-specific T cells, which are necessary during the effector phase and subsequent tumor elimination. We propose an in situ immunization strategy to enhance direct tumor antigen presentation by the lymphoma B cells via cluster of differentiation (CD)40 stimulation in order to sensitize B-cell lymphoma to programmed cell death protein 1/programmed death-ligand 1 (PD-L1) blockade therapy.MATERIALS AND METHODS: ITSELF is a multicenter, open-label, dose-escalation phase Ib trial of intratumoral selicrelumab, an agonistic anti-CD40 monoclonal antibody, every 3 weeks for three cycles in combination with intravenous atezolizumab, an antagonistic anti-PD-L1 monoclonal antibody, at 1200 mg every 3 weeks for three cycles followed by intravenous atezolizumab monotherapy for a total of 12 months in patients with relapsed/refractory B-cell lymphoma. RESULTS: Two patients with follicular lymphoma and two patients with diffuse large B-cell lymphoma were enrolled at the first dose level of 1 mg intratumoral selicrelumab. Those four patients received the three cycles of intratumoral selicrelumab in combination with intravenous atezolizumab. Patients did not develop severe adverse events related to the drugs or the intratumoral procedures. No or low-grade adverse events were reported and related to atezolizumab or to the combination therapy. All patients discontinued the treatment because of disease progression according to Lugano 2014 criteria on their first positron emission tomography scan disease evaluation at the end of cycle 3 (week 9). The trial was stopped prematurely because of issues with selicrelumab drug supply.CONCLUSION: The combination of 1 mg of intratumoral selicrelumab and 1200 mg of intravenous atezolizumab was safe for patients with relapsed/refractory B-cell lymphoma and led to some tumor stabilization or regression, although it did not result in objective tumor response
Degree bounds for linear differential equations and recurrences
No full textLinear differential equations and recurrences reveal many properties about their solutions. Therefore, these equations are well-suited for representing solutions and computing with special functions. We identify a large class of existing algorithms that compute such representations as a linear relation between the iterates of an elementary operator known as a pseudo-linear map. Algorithms of this form have been designed and used for solving various computational problems, in different contexts, including effective closure properties for linear differential or recurrence equations, the computation of a differential equation satisfied by an algebraic function, and many others. We propose a unified approach for establishing precise degree bounds on the solutions of all these problems. This approach relies on a common structure shared by all the specific instances of the class. For each problem, the obtained bound is tight. It either improves or recovers the previous best known bound that was derived by ad hoc methods
Cultural Production Reveals Transitions to Sustained Human Development in both European and Non-European Societies
No full textSustained human development is often seen as a recent phenomenon, primarily linked to Europe's Industrial Revolution. This perspective has shaped much of our historical understanding, but it relies on a limited set of economic indicators with restricted temporal and geographic coverage. In this article, we introduce Cultural Production as a complementary proxy for human development, particularly suited to long-term and cross-regional comparisons. Cultural production reflects the extent to which societies enable individuals to acquire knowledge, develop skills, and contribute to intellectual and artistic life-conditions closely tied to education, health, material security, and institutional support. We construct a global dataset tracking 122,634 distinct cultural producers (e.g., scientists, artists, writers) and apply ecological methods to estimate the number of unrecorded figures, correcting for differential survivorship bias. The resulting measure enables a broader and deeper reconstruction of human development across time and space. Our results challenge the prevailing view that meaningful development began only in modern Europe. We confirm that Western Europe experienced continuous gains from the 11th century onward, but we also uncover sustained growth in non-Western regions long before the 19th century. Japan shows multiple developmental phases, including a continuous rise after 1500 CE. In China, we trace human development back over 1,500 years, identifying major advances during the Han, Tang, and late imperial periods. In South and West Asia, we reveal marked progress under the Abbasid Caliphate and the Delhi Sultanate. Cultural Production also enables estimates of human development for Antiquity, showing developmental peaks in Classical Greece and Rome, though these were not sustained. Altogether, our findings suggest that all major regions, including non-European societies, transitioned from stagnation to sustained growth well before the Industrial Revolution-some as early as 1000 CE. These results suggest a more widespread and earlier pattern of human development across civilizations than previously recognized
Spectroscopic characterization of a remarkable temporally varying, triple-lensed quasar at z=2.67
No full textInternational audienceGravitationally lensed quasars are viable cosmic tools for constraining a diversity of fundamental astrophysical phenomena; They enable identification of faint, low-mass supermassive black holes, provide unique constraints on the intervening intergalactic or interstellar medium in their sightlines, and can be used to determine key cosmological quantities such as the Hubble constant, . However, they are rare phenomena, and it has proven difficult to define efficient, unbiased selection methods. In this study, we report the independent spectroscopic identification of a remarkable triple-lensed quasar at , identified based on astrometric measurements from the {\em Gaia} mission, previously identified in Pan-STARRS. Furthermore, a larger spectroscopic follow-up survey of {\em Gaia}-detected candidate lensed quasars. We characterize in detail the three mirror images of the quasar and their spatial and temporal spectroscopic coverage, with focus on the emission-line properties which shows variation across sigthlines and temporal evolution over the months spectroscopic campaign. We construct a lens model of the foreground source from a combination of the multiple spectra and deep optical imaging, providing a robust halo mass of . Based on the lens model, the time delay between each sightline is translated into an intrinsic quasar time, allowing us to construct a quasar timeseries over months with monthly cadence. Over months timescales the broad emission lines vary in both velocity offset and equivalent width (EW) as well as an overall increase in ionization. This exemplary triple-lensed quasars demonstrates the viability of identifying such rare lens configurations based purely on the astrometric measurements from the {\em Gaia} mission, which we here provide optimized selection criteria for, for future studies
On the space of subgroups of Baumslag-Solitar groups II : High transitivity
No full textA continuation of "On the space of subgroups of Baumslag-Solitar groups I: perfect kernel and phenotype", by Alessandro Carderi, Damien Gaboriau, François Le Maîitre, Yves Stalder (hal-03829832). 44 pages, 1 figureInternational audienceWe continue our study of the perfect kernel of the space of transitive actions of Baumslag-Solitar groups by investigating high transitivity. We show that actions of finite phenotype are never highly transitive, except when the phenotype is 1, in which case high transitivity is actually generic. In infinite phenotype, high transitivity is generic, except when |m|=|n| where it is empty. We also reinforce the dynamical properties of the action by conjugation on the perfect kernel that we had established in our first paper, replacing topological transitivity by high topological transitivity
La critique de la doctrine de l'État chrétien chez Ernst-Wolgang Böckenförde
No full textInternational audienceFervent catholique mais aussi grand défenseur de l'État, le juriste allemand Ernst-Wolgang Böckenförde a développé une importante réflexion sur les rapports entre politique et religion à l'heure de leur réarticulation dans le contexte moderne de la sécularisation. Conscient de l'extrême fragilité de l'État sécularisé, il appelle l'Église à se réconcilier avec son ancien adversaire. En retour, la religion doit se voir reconna\ⁱtre dans son rôle de la régulation de la liberté et de structuration de la société
